The involvement of mitogen‐activated protein (MAP) kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline

Abstract

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined. Both isomers stimulated the release of the non-amyloidogenic a-secretase form of soluble APP (sAPPalpha) from these cell lines. The increases in sAPPalpha, induced by TV3326 and TV3279, were dose-dependent (0.1-100 mM) and blocked by the hydroxamic acid-based metalloprotease inhibitor, Ro31-9790, suggesting mediation via a-secretase activity. Using several signal transduction inhibitors, we identified the involvement of protein kinase C (PKC), mitogen-activated protein (MAP) kinase, and tyrosine kinase-dependent pathways in the enhancement of sAPPalpha release by TV3326 and TV3279. In addition, both drugs directly induced the phosphorylation of p44 and p42 MAP kinase, which was abolished by the specific inhibitors of MAP kinase activation, PD98059 and U0126. These data suggest a novel pharmacological mechanism whereby these ChE inhibitors regulate the secretory processes of APP via activation of the MAP kinase pathway.

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

“…2). 21,53,136 In addition, the observation that ladostigil induces both BDNF and GDNF expression 115 may suggest a linkage between neurotrophic factors and the neuroprotective mechanism of action of ladostigil, as described previously for rasagilne and its propargyl moiety (FIG. 2).…”

“…79 Thus, the mechanism underlying these effects may involve both cholinergic and noncholinergic actions regulating APP synthesis and processing. Regulation of APP processing by ladostigil was demonstrated to involve PKC-and MAPK-dependent pathways 21 ( FIG. 2).…”

“…It has been demonstrating that ladostigil selectively reverses the behavioral and neurochemical effects induced by prenatal stress, 57 has antagonistic effect on scopolamine-induced impairments in spatial memory, 58 prevents memory deficits of rats induced by intracerebroventricular injection of STZ 59 or administering sodium azide. 114 These findings are allied with the elevation of the neurotrophic factors, brainderived neurotrophic factor (BDNF) and glial cell linederived neurotrophic factor (GDNF) mRNA expression, 115 and activation of PKC-MAPK signaling pathways by ladostigil, 21 since previous studies demonstrated that neurotrophic factors play critical roles in the development and function of neurons and may serve as regulatory factors for synaptic transmission, learning, and memory. 116,117 Thus, it has been proposed that several neurodegenerative disorders, such as PD, AD, and Huntington's disease are linked to a lack of trophic factor support in those neurons and brain areas associated with these diseases.…”

“…Nonetheless, previous studies demonstrating that rasagiline, as well as its propargyl moiety, promoted neuronal survival mediated by PKC-, MAPK-dependent activation associated with Bcl-2 family members 18 and mitochondrial membrane stabilization, 52,104 and thus might also have a crucial role in the neuroprotective activity of ladostigil. Also, ladostigil induced stimulatory effects on PKC and MAPK cascades 21 (FIG. 2), promoting the phosphorylation of p44 and p42 MAPK, which was abolished by specific inhibitors of MAPK activation.…”

“…2), promoting the phosphorylation of p44 and p42 MAPK, which was abolished by specific inhibitors of MAPK activation. 21 ERK activation in the central nervous system has been implied in mammalian synaptic plasticity and learning. 113 Thus, the effect of ladostigil on ERK activation could make ladostigil a potential valuable drug for the treatment of different types of dementia.…”